Everolimus (RAD001) is an orally active derivative of rapamycin that inhibits the Ser/Thr kinase, mTOR (mammalian target of rapamycin).[1]
In vitro activity of everolimus it displayed that the dose-dependent inhibition of cell growth by everolimus using methylene blue staining after 96 hours of incubation in four different human tumor cell lines, which can be regarded as sensitive (HCT-15, A549) and insensitive (KB-31 and HCT-116).[1] In vitro efficacy test, antiproliferative concentrations of RAD001 resulted in total dephosphorylation of S6K1 and the substrate S6 and a shift in the mobility of 4E-BP1, with IC50 of 0.7 nmol/L and 1,778 nmol/L in both the sensitive murine B16/BL6 melanoma and the insensitive human cervical KB-31,respectively.[2] In vitro study, combination gemcitabine (100 nM) with everolimus (0.05-2 μM) had significantly antiproliferative effect with an arrest of cell cycle at S phase.[3]
In vivo experimental it shown that everolimus is very well tolerated with no obvious clinical signs of toxicity; even when treating for up to 60 mg/kg per day by oral gavage the maximum tolerated dosage was not reached. In vivo efficacy study, daily orally treatment with everolimus (0.5 or 2.5 mg/kg) dose-dependently inhibited growth, and using a higher dose of 5 mg/kg once or twice per week also showed similar antitumor efficacy in the rat CA20498 model.[1] In vivo, treatment with 0.1-10 mg/kg/d RAD001 dose-dependently increased the hemoglobin content but reduced the Tie-2 content and this was significant for VEGF stimulation but not bFGF stimulation.[2]
References:
[1].O'Reilly T, McSheehy PM. Biomarker Development for the Clinical Activity of the mTOR Inhibitor Everolimus (RAD001): Processes, Limitations, and Further Proposals. Transl Oncol. 2010 Apr;3(2):65-79.
[2].Lane HA, et al. mTOR inhibitor RAD001 (everolimus) has antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor. Clin Cancer Res. 2009 Mar 1;15(5):1612-22.
[3].Pinto-Leite R, et al. Everolimus enhances gemcitabine-induced cytotoxicity in bladder-cancer cell lines. J Toxicol Environ Health A. 2012;75(13-15):788-99.
依维莫司 (RAD001) 是一种具有口服活性的雷帕霉素衍生物,可抑制 Ser/Thr 激酶 mTOR（雷帕霉素的哺乳动物靶标）。[1]
依维莫司的体外活性显示,在四种不同的人类肿瘤细胞系中孵育 96 小时后,使用亚甲蓝染色依维莫司对细胞生长的剂量依赖性抑制,可视为敏感（HCT-15、A549 ) 和不敏感（KB-31 和 HCT-116）。[1]在体外功效测试中,抗增殖浓度的 RAD001 导致 S6K1 和底物 S6 的完全去磷酸化以及 4E-BP1 的迁移率发生变化,在敏感小鼠 B16/BL6 中的 IC50 分别为 0.7 nmol/L 和 1,778 nmol/L分别对黑色素瘤和不敏感的人宫颈 KB-31。[2] 体外研究表明,吉西他滨 (100 nM) 与依维莫司 (0.05-2 μM) 的组合具有显着的抗增殖作用,并可阻滞细胞周期在S期。[3]
体内实验表明,依维莫司的耐受性非常好,没有明显的临床毒性迹象；即使通过口服强饲法以每天高达 60 mg/kg 的剂量进行治疗,也未达到最大耐受剂量。体内功效研究表明,每日口服依维莫司（0.5 或 2.5 mg/kg）剂量依赖性地抑制生长,每周一次或两次使用更高剂量的 5 mg/kg 在大鼠 CA20498 模型中也显示出相似的抗肿瘤功效。 [1] 在体内,用 0.1-10 mg/kg/d RAD001 剂量依赖性地增加血红蛋白含量但降低 Tie-2 含量,这对 VEGF 刺激有显着意义,但对 bFGF 刺激没有意义。 [2]